Enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants BA.4 and BA.5 (preprint)

SARS-CoV-2 adaptation to its human host is evidenced by the emergence of new viral lineages with distinct genotypic and phenotypic characteristics, termed variants of concern (VOCs). Particular VOCs have become sequentially dominant globally (Alpha, Delta, Omicron) with each evolving independently from the ancestral Wuhan strain. Omicron is notable for its large number of Spike mutations found to promote immune escape and re-infection. Most recently, Omicron BA.4 and BA.5 subvariants have emerged with increasing levels of adaptive immune escape threatening vaccine effectiveness and increasing hospitalisations. Here, we demonstrate that the most recent Omicron variants have enhanced capacity to antagonise or evade human innate immune defenses. We find Omicron BA.4 and BA.5 replication is associated with reduced activation of epithelial innate immune responses versus earlier BA.1 and BA.2 subvariants. We also find enhanced expression of innate immune antagonist proteins Orf6 and N, similar to Alpha, suggesting common pathways of human adaptation and linking VOC dominance to improved innate immune evasion. We conclude that Omicron BA.4 and BA.5 have combined evolution of antibody escape with enhanced antagonism of human innate immunity to improve transmission and possibly reduce immune protection from severe disease.

Mutations that adapt SARS-CoV-2 to mustelid hosts do not increase fitness in the human airway. (preprint)

SARS-CoV-2 has a broad mammalian species tropism infecting humans, cats, dogs and farmed mink. Since the start of the 2019 pandemic several reverse zoonotic outbreaks of SARS-CoV-2 have occurred in mink, one of which reinfected humans and caused a cluster of infections in Denmark. Here we investigate the molecular basis of mink and ferret adaptation and demonstrate the spike mutations Y453F, F486L, and N501T all specifically adapt SARS-CoV-2 to use mustelid ACE2. Furthermore, we risk assess these mutations and conclude mink-adapted viruses are unlikely to pose an increased threat to humans, as Y453F attenuates the virus replication in human cells and all 3 mink-adaptations have minimal antigenic impact. Finally, we show that certain SARS-CoV-2 variants emerging from circulation in humans may naturally have a greater propensity to infect mustelid hosts and therefore these species should continue to be surveyed for reverse zoonotic infections.